US7511023B2 - Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof - Google Patents

Anticancer drug-chitosan complex forming self-aggregates and preparation method thereof Download PDF

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US7511023B2
US7511023B2 US10/473,629 US47362903A US7511023B2 US 7511023 B2 US7511023 B2 US 7511023B2 US 47362903 A US47362903 A US 47362903A US 7511023 B2 US7511023 B2 US 7511023B2
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anticancer drug
chitosan
adriamycin
chitosan complex
drug
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US20040138152A1 (en
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Ick Chan Kwon
In-San Kim
Seo Young Jeong
Hesson Chung
Yong Woo Cho
Yoen Ju Son
Chong Rae Park
Sang Bong Seo
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Korea Advanced Institute of Science and Technology KAIST
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6907—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an anticancer drug-chitosan complex forming self-aggregates and the preparation method thereof. More precisely, the present invention relates to the anticancer drug-chitosan complex forming self-aggregates in aqueous media composed of a hydrophobic anticancer agent and a hydrophilic chitosan, and the preparation method thereof.
  • the anticancer drug-chitosan complex of the present invention not only works selectively against target tumor tissue but also continues to release the medicine over a long period of time. Besides, the anticancer drug-chitosan complex could have greater amount of drug by adding the anticancer drug into self-aggregates, which is generally limited by chemical bond. Therefore, the anticancer drug-chitosan complex of the present invention can be effectively used for the cancer chemotherapy.
  • Anticancer chemotherapy was set about progressing as choriocarcinoma was cured completely by using methotrexate.
  • anticancer drugs show anticancer effect by suppressing the synthesis of nucleic acid of tumor cells or defunctioning the nucleic acid by directly combining with the nucleic acid. However, they have serious side effects such as bone marrow depression, gastrointestinal damage and lose hair since these anticancer drugs work not only tumor cells but also for normal cells.
  • anticancer drugs do not selectively work for only tumor cells. That is; anticancer drugs are working for every cells showing fast division or proliferation (bone marrow cells, epitherial cells of stomach and intestines, hair follicle cells, etc.), causing almost every cancer patients to be suffering from side effects such as bone marrow depression, gastrointestinal trouble, and lose hair, etc. Nevertheless, the anticancer drugs have therapeutic effect against cancer because tumor cells respond more sensitively than normal cells, so that more tumor cells are destroyed than normal cells, in addition, normal cells are regenerated faster than tumor cells. Meanwhile, besides the anticancer effect, those anticancer drugs also have anti-immune effect. Thus, it is another use of anticancer drugs to be provided to patients who need organ transplantation for the purpose of eliminating rejection symptoms after transplantation. But the danger of infection should be considered for cancer patients since those drugs drop immunity.
  • anticancer drugs About 50 anticancer drugs have been widely used so far. These drugs are classified according to their reaction mechanism and components. Among them, adriamycin, commonly called doxorubicin, is highly effective for the treatment of malignant lymphoma, acute myeloid leukemia, soft tissue osteosarcoma, breast cancer, ovarian cancer, lung cancer, bronchial cancer, bladder cancer, digestive system cancer, etc. Although it is a very effective anticancer drug, it still presents such side effects as severe bone marrow depression, hypofunction of heart and kidney, and outflow of blood from blood vessels into tissues ( N. Eng. J. Med., 1981, 305, 139).
  • Cancer chemotherapy is very limited because of the toxic side effects of anticancer drugs. As explained above, side effects results from the fact that the anticancer drugs used in chemotherapy lack efficient selectivity for tumor cells. To suppress the toxic side effects of the anticancer drugs to normal cells and to improve their efficiency toward malignant cells, lots of studies have been carried out.
  • the preferable methods are using micelle or microsphere as a carrier of anticancer drug and conjugating anticancer drugs to polymeric carriers.
  • the first method that uses micelle or microsphere as a carrier of anticancer drug is to reduce side effects of cancer treatment by inserting anticancer drug into micelle or microsphere and letting it release slowly.
  • anticancer drug When anticancer drug is administered separately, it works in a short period in large quantities, by which side effects are caused.
  • This method is a good try to reduce those side effects by inducing slow release of the anticancer drug under the condition of enveloped in micelle or microsphere ( Pharm. Res., 1983, 15, 1844).
  • the second method is to produce anticancer drug-polymer complex by combining the drug with polymer.
  • Side effects are caused from the fact that the anticancer drugs used in the present cancer chemotherapy lack efficient selectivity for tumor cells.
  • studies of conjugating anticancer drugs to polymeric carriers have been carried out as one promising approach to suppress the side effects of the anticancer drugs to normal cells and to improve their efficiency toward tumor cells.
  • Expected advantageous features of this method are preferable tissue distribution of drug given by the character of the polymeric carrier, prolonged half-life of drug. in plasma, and controlled drug release from the polymeric carrier by adjustment of the chemical properties of the bond between the drug and the carrier.
  • immunoglobulins are most widely used as the carrier due to their high specificity and wide applicability to many kinds of tumor cells.
  • Utility of immunoglobuline as the polymeric carrier is, however, restricted by its chemical and physical properties.
  • modification of immunoglobulins by anticancer drugs often leads to precipitation due to hydrophobicity of the drugs.
  • modification procedures are limited to ones performed in mild conditions to avoid denaturation of the immunoglobulins during modification.
  • the polymeric carrier of the drug can be freely designed using many kinds of synthetic polymers available today, and various organic reactions can be used to introduce drug to the synthetic polymeric carrier.
  • synthetic polymers such as poly(N-2-(hydroxypropyl)methacrylamide), poly(divinyl ether-co-maleic anhydride), poly(styrene-co-maleic anhydride), dextran, poly(ethylene glycol), poly(L-glutamic acid), poly(aspartic acid) and poly(L-lysine).
  • cancer can be treated.
  • tumor tissues more blood vessels are generated than in normal tissues in order to get enough nutrition for the growth of tumor cells.
  • the blood vessels in tumor tissues have bigger size than those in normal tissues but their structure is defective. Drainage through a lymphatic duct is also very limited comparing normal tissues. Therefore, polymers easily permeate into tumor tissues but hardly be excreted from tumor tissues. This specific phenomenon showed in tumor tissues is called enhanced permeability and retention (EPR) effect ( Adv. Drug Deliv. Rev., 2000, 65, 271).
  • EPR enhanced permeability and retention
  • the anticancer drug-polymer complex forming self-aggregates is expected to have a large diameter, as compared with unbound drug, which is a small molecule.
  • the polymeric drug having ideal diameter is expected to circulate in the blood stream without embolization at capillaries, to escape from excretion in kidney, and to permeate into the target cells through blood vessels. And this self-aggregates form is expected to help protect the conjugated drug from enzymatic attack in plasma by concealing the conjugated drug with the polymer.
  • chitin is a natural polymer comprising (1 ⁇ 4)- ⁇ -glycoside bond in which N-acethyl-D-glucosamine units are repeated and is generally found in outer coat of insects including invertebrate Crustacea and cell wall of fungi.
  • Chitosan is a basic polysaccharide generated through N-deacethylation by treating chitin with the high concentration of alkali. Chitosan has been known to be superior to other synthetic polymers in cell adsorption capacity, biocompatibility, biodegradability and plasticity.
  • the present inventors have synthesized a novel anticancer drug-chitosan complex having strong points of micelle by making anticancer drug react with a polymer directly to form self-aggregates and making the anticancer drug be induced therein, which is different from the way of inserting anticancer drug into micelle. And, the present invention has been accomplished by confirming that the anticancer drug-chitosan complex can release the drug slowly and continuously, and can be controlled drug release by adjustment of the chemical properties of the bond between the drug and the chitosan, resulting in high selectivity against tumor tissues.
  • FIG. 1 is a graph showing the mean diameter and size distribution of adriamycin-chitosan complex of the present invention in aqueous solution measured by light scattering;
  • FIG. 2 is a set of transmission electron microscopy photographs of the adriamycin-chitosan complex of the present invention
  • FIG. 3 is a graph showing the different releasing level of adriamycin according to the pH from the adriamycin-chitosan complex of the present invention.
  • the present invention provides an anticancer drug-chitosan complex forming self-aggregates.
  • the present invention also provides a preparation method of the above anticancer drug-chitosan complex.
  • the present invention provides an anticancer drug-chitosan complex forming self-aggregates.
  • every kinds of chitosan having 10 3 -10 6 MW can be used as a carrier of anticancer drug, and soluble chitosan having high biodegradability and biocompatibility is preferred.
  • glycol chitosan with enhanced solubility by introducing glycol group is more preferred.
  • most hydrophobic anticancer drugs can be used for the anticancer drug-chitosan complex of the present invention, and especially, adriamycin is preferred.
  • the preferable size of the anticancer drug-chitosan complex of the present invention is 1 nm-2,000 nm. Especially, 10 nm-80 nm is more preferred.
  • the anticancer drug-chitosan complex of the present invention probably includes a linker additionally dissolved in an acidic condition.
  • a linker cis-aconitic anhydride, glutaric anhydride, succinic anhydride, oligopeptide and benzoyl hydrazone are can be used, and especially, pH-sensitive cis-aconitic anhydride is preferred ( Biochem. Biophys. Res. Comm., 1981, 102, 1048).
  • the anticancer drug-chitosan complex of the present invention is forming micelle-like, round-shaped self-aggregates in aqueous media due to the amphiphilicity of the complex by the hydrophobic group of anticancer drug and the hydrophilic group of chitosan.
  • the size of anticancer drug-chitosan complex of the present invention varies according to the amount of included anticancer drug and the possible amount of included anticancer drug is 1-70 weight %.
  • the present inventors used the above anticancer drug-chitosan complex as an anticancer drug carrier, which include the drug forcefully therein.
  • every kind of hydrophobic anticancer drugs can be used as an anticancer drug.
  • adriamycin, taxol, cis-platin, mitomycin-C, daunomycin and 5-fluorouracil are more preferred.
  • the preferable diameter of anticancer drug-chitosan complex containing anticancer drug inside is 1 nm-2,000 nm, and the range between 10 nm and 800 nm is more preferred.
  • anticancer drug-chitosan complex of the present invention is composed of hydrophobic anticancer drug and especially some hydrophilic parts of the anticancer drug are combined with chitosan, which cause strong hydrophobicity inside of the complex. Therefore, anticancer drug-chitosan complex of the present invention provides easy access for hydrophobic anticancer drug to the inside of the complex and could increase the amount of the drug. Either the same anticancer drugs can be used for both composing anticancer drug-chitosan complex and being inserted inside of the complex. And also, many different kinds of anticancer drugs can be inserted in anticancer drug-chitosan complex all together. Owing to the similarity of properties between anticancer drug-chitosan complex composing material and inserted anticancer drug therein, this complex has greater effect as a carrier than any other carrier has.
  • the anticancer drug-chitosan complex of the present invention has high selectivity against tumor tissues with enhanced permeability and retention (EPR) effect, so that it can be accumulated in tumor tissues with greater amount to effectively work for target cells, comparing to small molecular weight anticancer drugs.
  • the complex is also forming micelle-like round-shaped self-aggregates in aqueous media, which is caused by hydrophobic anticancer drug combined with hydrophilic chitosan used as a major chain.
  • micelle is a round-shaped aggregate formed by molecules having both hydrophobic group and hydrophilic group in aqueous media. At this time, hydrophilic group is aggregating outside the formed aggregate and hydrophobic group is gathering inside ( Adv. Drug Deliv.
  • This aggregate has been widely used as an carrier of various hydrophobic anticancer drugs.
  • This kind of drug delivery system using amphiphilic polymer forming self-aggregates showed high selectivity against target cells and remarkably reduced cytotoxicity to normal cells.
  • this system makes the drug be retained long enough and be released slowly and continuously resulting in an effective use for the treatment of serious disease like cancer.
  • the anticancer drug-chitosan complex of the present invention is an anticancer drug-polymer complex and an anticancer drug carrier having high selectivity against tumor tissues, having various advantages of micelle, and having capacity to release the drug continuously. Therefore, the anticancer drug-chitosan complex of the present invention can be effectively used as an anticancer drug having a strong anticancer effect.
  • the present invention also provides a preparation method of the above anticancer drug-chitosan complex.
  • the preparation method of the anticancer drug-chitosan complex of the present invention comprises following steps:
  • adriamycin is used as hydrophobic anticancer drugs.
  • a linker cis-aconitic anhydride, glutaric anhydride, succinic anhydride, oligopeptide and benzoyl hydrazone are can be used, and especially, pH-sensitive cis-aconitic anhydride is preferred ( Biochem. Biophys. Res. Comm., 1981, 102, 1048).
  • Cis-aconitic anhydride used for the combining anticancer drug with chitosan is a linker which is cut in acidic pH condition and release the anticancer drug. Tumor tissues show lower pH than normal tissues. Thus, this pH-sensitive cis-aconitic anhydride can improve the selectivity of anticancer drug against tumor tissues, and relieve the cytotoxicity to normal tissues, which has been the biggest problem of anticancer drugs.
  • glycol chitosan wherein glycol group is introduced is preferred.
  • the anticancer drug-chitosan complex of the present invention can be prepared by directly combining anticancer drug with chitosan or by linking anticancer drug to chitosan using a linker; the later is preferred.
  • the preparation method of anticancer drug-chitosan complex of the present invention includes the loading procedure of the anticancer drug into the inside of anticancer drug-chitosan complex forming self-aggregates.
  • Adriamycin, taxol, cis-platin, mytomycin-C, daunomycin and 5-fluorouracil are the examples of anticancer drug to be loaded into the inside of anticancer drug-chitosan complex. Loading by chemical bonding is limited to 10% at best, however, by the physical loading, the loading quantity of anticancer drug can be enhanced up to 60%, resulting in the increase of anticancer drug contents over the limitation of chemical bonding.
  • cis-aconityl adriamycin In order to prepare cis-aconityl adriamycin, the present inventors dissolved 13.46 mg of cis-aconitic anhydride (Chemical Formula 2) in 0.5 ml of dioxane and then dissolved 10 mg of adriamycin (Chemical Formula 1) in 350 ⁇ l of pyridine. After then, the present inventors added the cis-aconityl solution into adriamycin solution and let it be reacted at 4° C. or 24 hours.
  • reaction mixture was scattered into 5 ml of chloroform and 5% NaHCO 3 solution, and stirred strongly. Then, chloroform layer in the bottom was removed and the rest solution was extracted with ethyl acetate, after which solvent was evaporated, resulting in the preparation of cis-aconityl adriamycin.
  • the reaction procedure is summarized in the ⁇ Reaction Formula 1>.
  • Glycol chitosan was dissolved in 10 ml of water at the concentration of 1 W % and then 10 ml of methanol was added thereto.
  • 3 mg of cis-aconityl adriamycin was dissolved in 1 ml of DMF, which was slowly loaded into glycol chitosan solution.
  • 7 mg of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (EDC) and 5 mg of N-hydrosuccinimide (NHS) were dissolved in 1 ml of methanol, which was added into the reaction mixture and stirred at room temperature for 24 hours.
  • reaction mixture was dialyzed for 2 days to remove the unreacted cis-aconityl adriamycin and then freeze-dried, resulting in the preparation of adriamycin-chitosan complex of the present invention ( FIGS. 1 and 2 ).
  • the above reaction procedure was summarized in the following ⁇ Reaction Formula 2>.
  • the amount of adriamycin contained in adriamycin-chitosan complex depends on the amount of cis-aconityl adriamycin.
  • Cis-aconityl adriamycin and glycol chitosan were reacted for 6 hours. And, the same method as the above ⁇ 1-2> was performed for the rest of the procedure to prepare adriamycin-chitosan complex of the present invention.
  • Cis-aconityl adriamycin and glycol chitosan were reacted for 12 hours. And, the same method as the above ⁇ 1-2> was performed for the rest of the procedure to prepare adriamycin-chitosan complex of the present invention.
  • Cis-aconityl adriamycin and glycol chitosan were reacted for 18 hours. And, the same method as the above ⁇ 1-2> was performed for the rest of the procedure to prepare adriamycin-chitosan complex of the present invention.
  • Cis-aconityl adriamycin and glycol chitosan were reacted for 48 hours. And, the same method as the above ⁇ 1-2> was performed for the rest of the procedure to prepare adriamycin-chitosan complex of the present invention.
  • the amount of adriamycin contained in adriamycin-chitosan complex depends on the reaction time between cis-aconityl adriamycin and glycol chitosan.
  • adriamycin-chitosan complex forming self-aggregates containing adriamycin inside the present inventors dissolved 1 mg of adriamycin in 1 ml chloroform solution and then added triethylamine thereto. 5 mg of adriamycin-chitosan complex of the present invention was dissolved in 10 ml of water, and then the above adriamycin solution was slowed loaded thereto, followed by 24 hours stirring. At this time, let the vessel opened and contacted air for the evaporation of added chloroform.
  • Adriamycin- chitosan Amount of Loading complex/water Adriamycin loading effect (mg/ml) (mg) (w/w %) (%) 5 mg/10 ml 1 mg 18.9 W % 94.33% 5 mg/10 ml 2 mg 38.9 W % 97.23%
  • the present inventors dissolved 1 mg of adriamycin in 1 ml chloroform solution. And, the same method as the above Example 10 was performed for the rest of the procedure to prepare adriamycin-chitosan complex forming self-aggregates containing adriamycin therein (Table 1).
  • adriamycin-chitosan complex containing taxol 1 mg was dissolved in 1 ml DMF in order to prepare adriamycin-chitosan complex containing taxol inside.
  • 5 mg of adriamycin-chitosan complex of the present invention was dissolved in 10 ml of water, and then the above taxol solution was slowly loaded thereto, followed by 24 hours stirring. 24 hours later, dialysis was performed for every solution with a MWCO 3500 membrane for 2 days in order to eliminate remaining taxol which didn't permeate into the inside of adriamycin-chitosan complex. After the dialysis, the solution was freeze-dried, resulting in the preparation of adriamycin-chitosan complex containing taxol therein.
  • the present inventors dissolved 2 mg of taxol in 1 ml of DMF. And, the same method as the above Example 12 was performed for the rest of the procedure to prepare adriamycin-chitosan complex forming self-aggregates containing taxol therein.
  • the present inventors have observed the releasing level of adriamycin according to the pH from the adriamycin-chitosan complex of the present invention.
  • adriamycin-chitosan complex was dispersed into water until the concentration reached at 2 mg/ml, and then 500 ⁇ l of adriamycin-chitosan complex solution was enveloped in cellulose dialysis membrane (MWCO 12,000-14,000). After soaking thereof in each pH 4 and pH 7 water, the present inventors stirred thereof at 37° C. with 150 rpm and obtained releasing solution according to the time-table to measure the amount of released adriamycin with a spectrophotometer.
  • the amount of released adriamycin was gradually increased in both cases of pH 4 and pH 7 as time went by. But when being soaked in pH 4 water solution, the adriamycin-chitosan complex of the present invention released much more adriamycin comparatively, suggesting that the adriamycin-chitosan complex can be effectively used for the treatment of cancer by releasing adriamycin properly to the tumor-growing area which shows generally acidic condition.
  • the anticancer drug-chitosan complex of the present invention has prolonged drug-releasing time by forming self-aggregates, enhanced selectivity against tumor tissues, and increase the amount of drug by adding the anticancer drug into the inside of self-aggregates physically. Therefore, the anticancer drug-chitosan complex of the present invention can be effectively used for cancer chemotherapy.

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US20100286080A1 (en) * 2007-02-09 2010-11-11 The Jordanian Pharmaceutical Manufacturing Co. Aqueous composition comprising chitosan and an acidic drug
US20100323958A1 (en) * 2007-02-21 2010-12-23 Cutanea Life Sciences, Inc. Methods of Use of Biomaterial and Injectable Implant Containing Biomaterial
US20110136722A1 (en) * 2008-05-29 2011-06-09 Pronexx Co., Ltd. Drug Delivery Carrier
US20160310516A1 (en) * 2015-03-17 2016-10-27 University-Industry Cooperation Group Of Kyunghee University Conjugate of ginsenoside compound k and glycol chitosan and an anti-tumor use thereof

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WO2006075881A1 (en) 2005-01-14 2006-07-20 Korea Institute Of Science And Technology Cholanic acid-chitosan complex forming self-aggregates and preparation method thereof
KR100791414B1 (ko) * 2006-07-22 2008-01-07 광주과학기술원 항암제에 대한 경점막 운반 시스템
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